Schistosomiasis, a disease that afflicts 200 million people, is caused by helminth parasites of the genus Schistosoma. Schistosomes are complex metazoan pathogens that belong to an early diverging branch of the Bilateria, the Lophotrochozoans. Little is known of the molecular basis of cell to cell communication in animals in this group, but targeted studies and genome sequencing efforts have revealed that, not surprisingly, schistosomes contain some of the intercellular signaling systems that are found in higher order metazoa. Amongst these, we are particularly interested in the transforming growth factor 2 (TGF2) pathways. Elucidating the role(s) of this pathway in schistosome biology will be the goal of this proposal. Central to our view of what the TGF2 pathway might be doing in schistosomes has been our failure to identify a gene for a TGF2 ligand in these organisms, which led us to hypothesize that the TGF2 signaling pathway in schistosomes evolved to receive signals from host TGF2 ligands, a concept that was given credence by findings that schistosome TGF2 receptors can respond to human TGF2 ligands. Recently however, we made a breakthrough by identifying two schistosome TGF2 family members, SmInAct, which is a TGF2 homologue, and SmBMP, a member of the Bone Morphogenetic Protein subfamily of TGF2 ligands. Based on these published reports and our preliminary data we hypothesize that the TGF2 signaling pathway plays two distinct roles in schistosomes: 1) in embryogenesis, and 2) in the maintenance of the surface tegument. To address these hypotheses we will: 1) Explore the role of SmInAct in female reproductive potential and in embryogenesis; 2) Explore the role of TGF2 ligands in schistosome tegument biology, and 3) Explore the regulation of expression of TGF2 ligands. Our ability to address these issues has improved dramatically recently through the development of techniques for inhibiting endogenous gene expression and expressing transgenes in schistosomes, and we intend to make full use of these technologies in this proposal. We believe that our proposal addresses new and novel areas of schistosome biology and has the potential to identify new targets for chemotherapy. This is important since we currently have broad access to only one drug, praziquantel, for the treatment of schistosomiasis and consequently the potential for the development of resistance to this drug must be considered high. [unreadable] [unreadable] [unreadable]